Huntington disease (HD) is a well-defined hereditary disorder which is characterized by neuronal degeneration and progressive disability. Only palliative thereapies are available. Although the pathogenesis of HD remains obscure, striatal and pallidal neurons seem particularly vulnerable to a gradual process of cell death. Accumulating laboratory evidence suggests that neuronal degeneration in HD is related to a toxic process mediated by altered sensitivity to glutamate. To date, there have been no clinical studies assessing whether long-term pharmacotherapy might protect against neuronal degernation and thereby interrupt the relentless deterioration of HD patients. Because of evidence that glutamate exerts toxic effects on HD fibroblasts and kainate-treated neurons and that baclofen attenuates presynaptic glutamate release, we propose a long-term study to assess the protective influence of baclofen on the course of HD. Our preliminary studies indicate that baclofen is a safe drug which is well tolerated by HD patients. Using a double-blind format of evaluation, we plan to examine 60 minimally disable HD patients over a 3-year observation period. Subjects will be randomized to either baclofen or placebo thereapy and will be reevaluated at regular intervals in our Clinical Research Center. We will measure clinical decline in terms of functional capacities, clinical features (motoric, cognitive, psychiatric) and radiographic correlates of caudate atrophy. Baclofen concentrations will be measured periodically in blood and CSF in order to assess pharmacokinetic patterns and medication compliance. We anticipate that our proposed project will clarify the efficacy of baclofen as protective therapy in HD. We plan to generate new information regarding the clinical couse of HD which can be translated into substantive gains for HD patients and families. Finally, we expect that our study will provide a model for the prevention or postponement of clinical deterioration in HD.